Project summary: A number of viruses express homologs to various cellular proteins involved in the regulation of the immune response. This laboratory's long term goal is to further the understanding of the role of such viral-encoded cellular homologs in viral evasion of host immune responses. Epstein-Barr virus (EBV) is a significant, potentially oncogenic human pathogen. EBV encodes a homolog to the human interleukin 10 (IL-10) known as vlL-10. While a variety of effects of vlL-10 have been described in in vitro and in vivo assays, the role of vlL-10 in viral pathogenesis and latency in a model of infectious disease remains to be established. Such studies have been hampered by EBV's strictly limited host range. Therefore, we propose to utilize murine gammaherpesvirus (MHV) infection of mice to elucidate the role of vlL-10 in viral infection, pathogenesis, and latency. We have two specific aims. Aim 1 is to elucidate the role of vlL-10 in MHV pathogenesis and establishment of latency. We will generate a recombinant MHV (rMHV) containing the EBV vlL-10 gene and assess the pathogenic changes elicited by the expression of vlL-10 in MHV-infected mice. Specifically, we will observe the quantity of virus in lytic infection, enlargement of spleen, expansion of lymphocyte populations, and quantity of latently infected cells at various times post- infection. We anticipate that rMHV expressing vll_-10 will elicit a greater pathogenic effect and yield higher levels of latency than virus not expressing vlL-10. Aim 2 is to define the relative contributions of endogenous IL-10 and vlL-10 to MHV pathogenesis. We will utilize the rMHV strains to infect IL-10-deficient mice to assess the extent to which vlL-10 may substitute for endogenous IL-10. We anticipate that viral expression of vlL-10 in IL-10-deficient mice will mimic the role of endogenous IL-10 in wild-type mice and yield a high level of latent viral infection. Relevance: The primary objective of this study is to begin to explore a functional model that posits that vIL- 10 exhibits immune modulatory effects that assist in the establishment of latent viral infection. Mechanisms of immune tolerance to latently infected cells, to tumors, and to allografts may well .share common themes. A fuller understanding of any one mechanism may suggest therapies relevant to all.